Method of treating depression using di-substituted -&#39; -phenethylcarbamic acid esters

ABSTRACT

Novel di-substituted .beta.-phenethylcarbamic acid esters. The compounds are useful as antidepressants and anti-Parkinsonism agents.

[ 1 Apr. 8, 1975 1 METHOD or TREATING DEPRESSION usmc Dl-SUBSTITUTED-B-PHENETHYLCARBAMIC ACID ESTERS [75] Inventors: John Hans Biel, LakeBluff. Ill.:

Irwin L. Klundt, Brookfield. Wis.

[73] Assignee: Aldrich Chemical Company,

Milwaukee, Wis.

[221' Filed: Aug. 2, 1973 [21] Appl. No.: 385,010

Related US. Application Data [62] Division at Ser. No. 96.586. Dec. 9,1970. Pat. No.

[52] U.S. Cl. 424/300; 424/244; 424/285; 424/301 [51] Int. Cl...-.. A6lk27/00 [58] Field of Search 424/300; 260/271 C [56] p 4 References CitedUNITED STATES PATENTS 3.600.427 '8/19'71 Verbiscar 260/471 c PrimaryExaminer-Stanley Friedman Attorney, Agent, qr FirmR0bert L. Niblack;Joyce R. Krei; Vincent A. Mallare [57] Y ABSTRACT Novel di-substitut'edB-phenethylcarbamic acid esters. The compounds are useful asantidepressants and anti- Parkinsonism agents.

9 Claims, No Drawings METHOD OF TREATING DEPRESSION USING DI-SUBSTITUTED-B-PIIENETI-IYLCARBAMIC ACID ESTERS This is a division of applicationSer. No. 96,586 filed Dec. 9, 1970, now U.S. Pat. No. 3,801,624.

BACKGROUND OF THE INVENTION Until recently, patients suffering fromParkinsonism were treated with anticonvulsants, antispasmodics, centralnervous system stimulants, and the like, in an attempt to producetemporary amelioration of their complaints. In severe cases, surgicalprocedures were employed with some success. L-Dopa was the first singleagent found to be effective in reversing the akinesia and rigidity ofParkinsonism, particularly in severe cases. An increase in mentalalertness and wakefulness,

relief from depression, and an increase in intellect has also beenobserved in patients receiving L-Dopa.

While L-Dopa has produced some rather promising results in experimentaltherapy and is being used in a limited number of patients, it is notwell tolerated by'a number of patients. The most frequent side effectsare nausea, vomiting, postural hypotension, cardiac dysrhythmia andchoreiform movements. The abnormal,

. involuntary movements pose severe problems to the drugs continued usein approximately 50 percent of the patients. Furthermore, dopamineitself is not orally active and has a very short duration of action.Thus; the search for more effective, orally active, long-actinganti-Parkinson agents continues. It is an object of the presentinvention to provide such agents.

SUMMARY This invention relates to novel B-phenethylcarbamic acid estersrepresented structural formula: I

di-substituted bythe wherein: R and R are hydrogen, benzyl, substitutedbenzyl, or

wherein A is O, NH, or S, and R is lower alkyl, lower alkenyl, or loweralkynyl; and R is lower alkyl, lower alkenyl, lower alkynyl, lowerhaloalkyl, c'yclopropylmethyl, B-(Z-furyU-ethyl or azetidinyl; with thelimita- Lower alkenyl" refers to both straight and branched chainalkenyl groups containing from 2 to 5 carbon atoms, such as'vinyl,allyl, methallyl, l-pentenyl, and the like.

Lower alkynyl refers to C -C alkyl groups as defined above from whichtwo hydrogen atoms have been removed from each of two adjacent carbonatoms to produce acetylenic unsaturation; e.g., propargyl, 2- butynyl,l=pentynyl, and the like.

Substituted b'enzyl refers to a mono, di-, or trisubstituted ben zylmoiety substituted in the ortho, meta and/or para positions by a chloro,fluoro, iodo, bromo, or tri-fluoromethyl atom.

Halo includes chloro, fluoro, bromo, and iodo.

The anti-Parkinson activity of the above compounds was established usingthe Harmonyl (deserpidine) Antagonism Test. In the Harmony] test, miceare dosed Y orally with 50 mg/kg of deserpidine 24 hours prior to drugevaluationqln mice, deserpidine produces ptosis, hunched posture,sedation, catalepsy and rigidity. L- Dopa produces marked reversal ofthe above effects in mice. Antagonism of the deserpidine effects in miceare graded slight (1), moderate (2) or marked (3), based on the reversalof the Harmonyl effects. The compounds of the invention produce moderateto marked reversal in dosages of from 10 to 200 mg/kg of body weight.

The compounds are generally administered to mammalian Parkinsonismpatients in dosages of from 10 to 200 mg/kg of body weight daily,preferably in divided doses. While the compounds exhibit both oral andparenteral activity, the preferred route of administration is the oralroute. The oral LD of the compounds of this invention in mice areapproximately 6()0l .000 mg/kg.

The antidepressant activity of the compounds of this invention was firstestablished in the modified dopa test as described by Everett et al.,Fed. Proc., 23 p. 198 (1964). The compounds are useful as antidepressantagents when administered to depressed patients in dosages of from 10 to200 mg/kg of'body weightdaily, preferably in divided doses.

Representative compounds of the present invention include:'

3,4-Dibenzyloxy-B-phenethylcarbamic acid, furfu'ryl ester,

3,4-DihydroxyB-phenethylcarbamic acid, ethyl ester,

3,4-Dihydroxy-B-phenethylcarbamic acid, isopropyl ester,

3,4-Dihydroxy-B-phenethylcarba'mic acid, n-butyl ester,

3,4-Dibenzyloxy-B-phenethylcarbamic acid, B-trichloroethyl ester,3,4-Dibenzyloxy-B-phenethylcarbamic acid, isopropyl ester,

3,4-Dihydroxy-fi phenethylcarbamic acid, trichloro-- ethyl ester,3,4-Dihydroxy-B-phenethylcarbamic acid, 3- azetidinyl ester,3,4-Dibenzyloxy-B-phenethylcarbmic acid, cyclopro pylmethyl ester,3,4-Dithioethoxycarbonyl-B-phenethylcarbamic acid, ethyl ester3,4-Dimethoxycarbonyl-B-phenethylcarbamic acid,

methyl ester 3,4-Dipropargyloxycarbonyl-B-phenethylcarbamic acid,propargyl ester,

3,4-Diallyloxycarbonyl-B-phenethylcarbamic acid, lowed to stand at roomtemperature overnight, filtered, allyl ester and solvent removed invacuo and the residue purified The method of synthesis of the compoundsof this inby a Kugelrohr distillation to give 14 g (78%) of 3,4- ventionis represented by the following reactiondibenzyloxy-fi-phenethylisocyanate as a light yellow scheme. 5 oil, b.p.l80 (0.05 mm).

RC1 ca uo no CHO RO@CHO R H GH-N ao R0 R0 I no on -ca maco R' ROCCl 2 22 Pd/C/H O 5 no cs ca naco a' o CH -CH -NH I R0 R0 RACC ft.

0]. meet m V o ll moi Q CH -CH -NH CO R RACO R0 CH -CH -N C O Generallyspeaking, protocatechualdehyde. l, (Ald- I Analysis Calcd. for C H NO C,76.86; H, 5.89; N, rich Chemical Co.) is reacted with RCl (i.e., benzyl3.90; Found: C, 77.17; H, 5.75; N, 3.90 chloride, etc.) to prepare2-(wherein R=C H CH B. 3,4-Dibenzyloxy-B-phenethylcarbamic acid, isopro-2 is converted to the corresponding B-nitrostyrene, 3, pyl ester whichis treated with lithium aluminum hydride and the In a 50 ml flaskequipped with a magnetic stirrer and resulting amine 4 reacted-with anappropriate chloroa reflux condenser protected by a drying tube wereformate to prepare 5 (R=loweralkyl, etc.) or the placed 4.5 g (12.5mole) of 3,4-dibenzyloxy-B- amine 4 can be converted to the isocyanate 8and then phenethylisocyanate, 20 ml of benzene, 1.3 ml of dry reactedwith an appropriate alcohol to prepare 5. Reisopropanol and a crystal ofbicyclo[2,2,2] 1,4- moval of the catechol protecting group produces 6diazaoctane. The reaction was heated at reflux for 20 which can beconverted to 7(A=O, NH or S) by treathours. Removal of the solvent lefta residue which coning 6 with either an appropriate chloroformate or antained the unreacted isocyanate. The residue was redisisocyanate. solvedin 25 ml of benzene, 1.3 ml of isopropanol The following examplesfurther illustrate the present added and 2 drops of DBU(Aldrichl,3-diazabicyinvention. clo[5,4,0]undec-5 ene) added. This washeated to reflux for 24 hours. The reaction was cooled, diluted withEXAMPLE 1 25 ml of benzene, filtered and the solvent was removedPREPARATION OF in vacuo. The residue was dissolved in 150 ml of hot cy-3,4-DlBENZYLOXY B-PHENETHYLCARBAMIC clohexane and set aside tocrystallize. The white solid ACID, ISOPROPYL ESTER was filtered off anddried in vacuo to yield 2.1 g of 3,4- dibenzyloxy-B-phenethylcarbamicacid, isopropyl ester, m.p. 83C.

55 Analysis Calcd. for C .;H NO C, 74.44; H, 6.97; N,

3.34; Found: C, 74.68; H, 6.89; N, 3.41

A. 3,4-Dibenzyloxy-B-phenethylisocyanate In a 500 ml three necked flaskequipped with a gas inlet tube and a Claisen head for distillation wereplaced 18.5 g (0.05-mole) of benzyloxydopamine hydrochloride in 350 mlof toluene. This was heated to reflux and ml of toluene distilled off.The Claisen head was replaced with a reflux condenser equipped Thefollowing compounds were prepared according with a drying tube andphosgene was bubbled through to the method of Example 1 by replacingisopropanol the refluxing solution for 4 hours. The reaction was alwiththe appropriate alcohol.

EXAMPLES 2 9 l n 0 ca -ca -mic-oa,

Analvsis EX- Empirical (L1 c cl Found it R1 R R 11.1. Formula 0 n N c aN 2 ll 11 (CH3)2CH 91.5-92.5 c n uo 60.25 7.11 5.86 60.13 7.25 5.77 3 aa 001 011 155 157 c a m uo 40.21 3.68 4.12 40.48 3.84 4.14 4 a H A411118 119 0 11 110 62.07 6.81 5.57 62.20 6.51 5.59 5 H a 9 D 102 -104 0 1180, 63.42 7.7 5.28 63.40 7.99 5.71 6 ll c a cc a 127 129 C14H19N06 56.646.40 4.71 56.71 6.44 4.60 7 0 11 014 C 1-l Cl-I 011 001 127.5-128.5CZSHZACINOI 59.01 4.75 2.75 59.16 4.63 2.88 8 C H Cll c n ca ca(cn s0 830 51 80 74.44 6.97 3.34 74.68 6.89 3.41 9 0 11 011 0 11 611 ca w 71 73 Cl-I N0 73.36 6.11 3.06 73.36 5.97 3.1

EXAMPLE 1O the compositions, or by heating the compositions. They3,4-Dll-lYDROXY-B-PHENETHYLCARBAMIC ACID, ETHYL ESTER A solution of 45 gof 3,4-dibenzyloxy-B-phenethylcarbamic acid, ethyl ester, preparedaccording to the method of Example 1, in 200 ml of ethanol containing 3g of moist 10% Pd/C was hydrogenated at p.s.i. The reaction wasfiltered, evaporated to dryness and recrystallized from benzene to yield18.4 g of product, m.p. 99-l0l.

Analysis Calcd. for C l-l NQpC, 58.65; H, 6.71; N,

6.22; Found: C 58.63; H, 6.58, N, 5.98

The compounds useful in the practice of the present invention aregenerally formulated into pharmaceutical compositions comprising, as anactive ingredient, at least one of the active agents in association witha pharmaceutical carrier or diluent. The compounds useful in thepractice of the invention exhibit both oral and parenteral activity andcan be formulated in dosage forms for oral or parenteral administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. in such solid dosage forms, the activecompound is admixed with at least one inert diluent such as sucrose,lactose or starch. Such dosage forms can also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water.Besides inert diluents, such compositions can also include adjuvants,

such as wetting agents, emulsifying and suspending agents andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or nonaqueous solutions, suspensions oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil andinjectable organic esters such as ethyl oleate. Such dosage forms mayalso contain adjuvants such as preserving, wetting, emulsifying anddispersing agents. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, by incorporating sterilizing agentsinto the compositions, by irradiating can also be manufactured in theform of sterile solid compositions which can be dissolved in sterilewater, or some other sterile injectable medium immediately before use.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient shall be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect. on theroute of administration, and on the duration of the treatment.

We claim:

1. A method of relieving the systems of depression in a mammalianpatient in need of such treatment comprising the administration to saidpatient of a therapeutically effective amount of a compound of theformula:

wherein R and R are the same or different members of the groupconsisting of hydrogen or benzyl; and R, is loweralkyl, lowerhaloalkyl,cyclopropylmethyl or cyclopentyl.

2. A method in accordance withclaim 1 wherein the compound is3,4-dihydroxy-B-phenethylcarbamic acid, ethyl ester.

3. A method in accordance with claim 1 wherein the compound is3,4-dibenzyloxy-B-phenethyl-carbamic acid, ethyl ester.

4. A method in accordance with claim 1 wherein R, is loweralkyl.

5. A method in accordance with claim 1 wherein R is ethyl.

6. A method in accordance with claim 1 wherein R is iso-propyl.

7. A method in accordance with claim 1 wherein R is chloroethyl.

8. A method in accordance with claim 1 wherein R is cyclopropylmethyl.

9. A method in accordance with claim 1 wherein R is cyclopentyl.

1. A METHOD OF RELIEVING THE SYSTEMS OF DEPRESSION IN A MAMMALIANPATIENT IN NEED OF SUCH TREATMENT COMPRISING THE ADMINISTRATION TO SAIDPATIENT OF A THEREPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THEFORMULA:
 2. A method in accordance with claim 1 wherein the compound is3,4-dihydroxy-.beta.-phenethylcarbamic acid, ethyl ester.
 3. A method inaccordance with claim 1 wherein the compound is3,4-dibenzyloxy-.beta.-phenethyl-carbamic acid, ethyl ester.
 4. A methodin accordance with claim 1 wherein R.sub.4 is loweralkyl.
 5. A method inaccordance with claim 1 wherein R.sub.4 is ethyl.
 6. A method inaccordance with claim 1 wherein R.sub.4 is iso-propyl.
 7. A method inaccordance with claim 1 wherein R.sub.4 is chloroethyl.
 8. A method inaccordance with claim 1 wherein R.sub.4 is cyclopropylmethyl.
 9. Amethod in accordance with claim 1 wherein R.sub.4 is cyclopentyl.